The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

Erinc Hallacli; Can Kayatekin; Sumaiya Nazeen; Xiou H. Wang; Zoe Sheinkopf; Shubhangi Sathyakumar; Souvarish Sarkar; Xin Jiang; Xianjun Dong; Roberto Di Maio; Wen Wang; Matthew T. Keeney; Daniel Felsky; Jackson Sandoe; Aazam Vahdatshoar; Namrata D. Udeshi; D. R. Mani; Steven A. Carr; Susan Lindquist; Philip L. De Jager; David P. Bartel; Chad L. Myers; J. Timothy Greenamyre; Mel B. Feany; Shamil R. Sunyaev; Chee Yeun Chung; Vikram Khurana

doi:10.1016/j.cell.2022.05.008

The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

Erinc Hallacli
, Can Kayatekin
, Sumaiya Nazeen
, Xiou H. Wang
, Zoe Sheinkopf
, Shubhangi Sathyakumar
, Souvarish Sarkar
, Xin Jiang
, Xianjun Dong
, Roberto Di Maio
, Wen Wang
, Matthew T. Keeney
, Daniel Felsky
, Jackson Sandoe
, Aazam Vahdatshoar
, Namrata D. Udeshi
, D. R. Mani
, Steven A. Carr
, Susan Lindquist
, Philip L. De Jager

David P. Bartel, Chad L. Myers, J. Timothy Greenamyre, Mel B. Feany, Shamil R. Sunyaev, Chee Yeun Chung, Vikram Khurana

Research output: Contribution to journal › Article › peer-review

144 Scopus citations

Abstract

Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.

Original language	English (US)
Pages (from-to)	2035-2056.e33
Journal	Cell
Volume	185
Issue number	12
DOIs	https://doi.org/10.1016/j.cell.2022.05.008
State	Published - Jun 9 2022

Bibliographical note

Funding Information:
We thank all the members of ARCND community for their critical input on the paper, especially Drs. Dennis Selkoe, Greg Petsko, Ulf Dettmer, Charles Jennings, Vijay Kuchroo, Howard Weiner, and Tracy Young-Pearse. We thank Ulf Dettmer for the SNCA G51D construct, Lei Liu for PX459 plasmid, Lai Ding at BWH NeuroTechnology Studio for Fiji macros, Ping Xu at Yumanity Therapeutics for superb technical support, and Luigi Warren (Cellular Reprogramming) for reprogramming of iPSC. NGS was performed at the Whitehead Genome Technology core (overseen by Sumeet Gupta). We thank Dr. Alexander Drew for helping with quality control of the PPMI and PDBP sub-cohorts of AMP-PD. E.H. was supported by the HSFP (LT000717/2015-L), NIH (R21NS112858), and Aligning Science Across Parkinson's disease(ASAP-000472). D.F. is supported by the Koerner New Scientist Program from the Koerner Family Foundation. We thank Dr. Leon French for assistance with computational code for enrichment term consolidation for the ROSMAP analysis. W.W. and C.L.M. are supported by the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer's Association as well as Alzheimer's Research UK (ARUK), the Michael J. Fox Foundation for Parkinson's Research (MJFF), and the Weston Brain Institute (Weston) (BAND-19-615151). S. Sunyaev is supported by NIH R01MH101244 and NIH R35GM127131. V.K. is a NYSCF Stem Cell Robertson Investigator (NYSCF-R-I49) and a George C. Cotzias Fellow of the American Parkinson's Disease Association; both awards supported this work. Additional grants to V.K. that supported this work include Aligning Science Across Parkinson's Inititiative ASAP-000472, Brigham Research Institute Director's Transformative Award, DOD W81XWH-19-1-0695, Michael J. Fox Foundation, Multiple System Atrophy Coalition, and NIH R21NS112858 and R01NS109209. The authors also thank the Accelerating Medicines Partnership Parkinson's disease (AMP PD), a public-private partnership, which is managed by the Foundation for the National Institutes of Health (FNIH) and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson's Research, the National Institute of Neurological Disorders and Stroke, Pfizer, and Verily. E.H. C.K. and V.K. conceived of and designed the project. E.H. and V.K. wrote the manuscript with input from co-authors. E.H. conducted and analyzed all biochemical and cell-based assays with help from Z.S. X.H.W. S. Sathyakumar, and A.V.; C.K. and E.H. conducted yeast assays. V.K. C.Y.C. and X.J. oversaw iPSC reprogramming and genetic corrections. J.S. constructed the Ngn2 piggyBac plasmid, and cell lines were generated by A.V.; X.D. analyzed sequencing data for the mRNA stability experiment. D.F. and P.L.D. conducted the ROSMAP analysis. W.W. and C.L.M. conducted the BridGE analysis. R.D.M. M.T.K. and J.T.G. contributed brain PLA. S.N. and S.R.S. designed and conducted RVTT analysis. S. Sarkar and M.B.F. conducted the Drosophila experiments. C.Y.C. designed and conducted the SILAC experiments, and N.D.U. D.R.M. and S.A.C. performed the mass spectrometry and downstream analysis. E.H. prepared all the figures and analyzed the data with input from V.K. (except as otherwise noted). V.K. is a co-founder of and senior advisor to DaCapo Brainscience and Yumanity Therapeutics, companies focused on CNS diseases. C.Y.C. and X.J. contributed to this work as employees of Yumanity Therapeutics.

Funding Information:
We thank all the members of ARCND community for their critical input on the paper, especially Drs. Dennis Selkoe, Greg Petsko, Ulf Dettmer, Charles Jennings, Vijay Kuchroo, Howard Weiner, and Tracy Young-Pearse. We thank Ulf Dettmer for the SNCA G51D construct, Lei Liu for PX459 plasmid, Lai Ding at BWH NeuroTechnology Studio for Fiji macros, Ping Xu at Yumanity Therapeutics for superb technical support, and Luigi Warren (Cellular Reprogramming) for reprogramming of iPSC. NGS was performed at the Whitehead Genome Technology core (overseen by Sumeet Gupta). We thank Dr. Alexander Drew for helping with quality control of the PPMI and PDBP sub-cohorts of AMP-PD. E.H. was supported by the HSFP ( LT000717/2015-L ), NIH ( R21NS112858 ), and Aligning Science Across Parkinson’s disease ( ASAP-000472 ). D.F. is supported by the Koerner New Scientist Program from the Koerner Family Foundation . We thank Dr. Leon French for assistance with computational code for enrichment term consolidation for the ROSMAP analysis. W.W. and C.L.M. are supported by the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer’s Association as well as Alzheimer’s Research UK (ARUK), the Michael J. Fox Foundation for Parkinson’s Research (MJFF), and the Weston Brain Institute (Weston) ( BAND-19-615151 ). S. Sunyaev is supported by NIH R01MH101244 and NIH R35GM127131 . V.K. is a NYSCF Stem Cell Robertson Investigator ( NYSCF-R-I49 ) and a George C. Cotzias Fellow of the American Parkinson’s Disease Association ; both awards supported this work. Additional grants to V.K. that supported this work include Aligning Science Across Parkinson’s Inititiative ASAP-000472 , Brigham Research Institute Director's Transformative Award, DOD W81XWH-19-1-0695, Michael J. Fox Foundation , Multiple System Atrophy Coalition, and NIH R21NS112858 and R01NS109209 . The authors also thank the Accelerating Medicines Partnership Parkinson’s disease (AMP PD), a public-private partnership, which is managed by the Foundation for the National Institutes of Health (FNIH) and funded by Celgene , GSK , the Michael J. Fox Foundation for Parkinson’s Research , the National Institute of Neurological Disorders and Stroke , Pfizer , and Verily .

Funding Information:
The authors thank the NIH-designated data repository (dbGaP: The database of Genotypes and Phenotypes), and the submitting investigators who submitted data from the original studies to the dbGap repository: phs000196.v3.p1 (Dr. Haydeh Payami), phs000089.v3.p2 (Dr. Robert Brown, Dr. David Simon, Dr. Dennis Dickson, Dr. Matthew Farrer, Dr. Emily Gorbold, Dr. Ira Shoulson, Dr. John A. Hardy, Dr. Laura Marsh, Dr. Michael Okun, Dr. Ted Roghstein, Dr. Zbigniew Wszolek), phs000048.v1.p1 (Dr. Demetrius M. Maraganore), phs000126.v2.p1(Dr. Tatiana Foroud, Dr. Richard H. Myers), phs000918.v1.p1 (Dr. Andrew B. Singleton, Dr. Mike A. Nalls), phs000394.v1.p1 (Dr. Jeffery Vance), phs000127.v2.p1 (Dr. Orla Hardiman, Dr. Brendan Loftus, Dr. Daniel G. Bradley, Dr. Alex Evans), phs000344.v1.p1 (Dr. Bryan J. Traynor, Dr. Pentti J. Tienari), phs000101.v3.p1 (Dr. Bryan J. Traynor), and their primary funding organizations including National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Institute on Aging, Michael J. Fox Foundation, International Parkinson Disease Genomics Consortium, USAMRAA, Muscular Dystrophy Association, Science Foundation Ireland, Microsoft Research, the ALS Association, The Helsinki University Central Hospital, the Finnish Academy, the Finnish Medical Society Duodecim, Kuopio University. The authors also thank the AMP PD, a public-private partnership, which is managed by the FNIH and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson’s Research, the National Institute of Neurological Disorders and Stroke, Pfizer, and Verily.

Publisher Copyright:
© 2022 The Authors

Keywords

Lewy body disease
Parkinson's disease
Processing bodies
RNA-binding proteins
alpha-synuclein
iPSC
mRNA degradation
mRNA stability
rare variant
synucleinopathy

Publisher link

10.1016/j.cell.2022.05.008

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Cite this

Hallacli, E., Kayatekin, C., Nazeen, S., Wang, X. H., Sheinkopf, Z., Sathyakumar, S., Sarkar, S., Jiang, X., Dong, X., Di Maio, R., Wang, W., Keeney, M. T., Felsky, D., Sandoe, J., Vahdatshoar, A., Udeshi, N. D., Mani, D. R., Carr, S. A., Lindquist, S., ... Khurana, V. (2022). The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability. Cell, 185(12), 2035-2056.e33. https://doi.org/10.1016/j.cell.2022.05.008

Hallacli, E, Kayatekin, C, Nazeen, S, Wang, XH, Sheinkopf, Z, Sathyakumar, S, Sarkar, S, Jiang, X, Dong, X, Di Maio, R, Wang, W, Keeney, MT, Felsky, D, Sandoe, J, Vahdatshoar, A, Udeshi, ND, Mani, DR, Carr, SA, Lindquist, S, De Jager, PL, Bartel, DP, Myers, CL, Greenamyre, JT, Feany, MB, Sunyaev, SR, Chung, CY & Khurana, V 2022, 'The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability', Cell, vol. 185, no. 12, pp. 2035-2056.e33. https://doi.org/10.1016/j.cell.2022.05.008

@article{d3429c1e40454136a698576748c9d8d3,

title = "The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability",

abstract = "Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.",

keywords = "Lewy body disease, Parkinson's disease, Processing bodies, RNA-binding proteins, alpha-synuclein, iPSC, mRNA degradation, mRNA stability, rare variant, synucleinopathy",

author = "Erinc Hallacli and Can Kayatekin and Sumaiya Nazeen and Wang, \{Xiou H.\} and Zoe Sheinkopf and Shubhangi Sathyakumar and Souvarish Sarkar and Xin Jiang and Xianjun Dong and \{Di Maio\}, Roberto and Wen Wang and Keeney, \{Matthew T.\} and Daniel Felsky and Jackson Sandoe and Aazam Vahdatshoar and Udeshi, \{Namrata D.\} and Mani, \{D. R.\} and Carr, \{Steven A.\} and Susan Lindquist and \{De Jager\}, \{Philip L.\} and Bartel, \{David P.\} and Myers, \{Chad L.\} and Greenamyre, \{J. Timothy\} and Feany, \{Mel B.\} and Sunyaev, \{Shamil R.\} and Chung, \{Chee Yeun\} and Vikram Khurana",

note = "Funding Information: We thank all the members of ARCND community for their critical input on the paper, especially Drs. Dennis Selkoe, Greg Petsko, Ulf Dettmer, Charles Jennings, Vijay Kuchroo, Howard Weiner, and Tracy Young-Pearse. We thank Ulf Dettmer for the SNCA G51D construct, Lei Liu for PX459 plasmid, Lai Ding at BWH NeuroTechnology Studio for Fiji macros, Ping Xu at Yumanity Therapeutics for superb technical support, and Luigi Warren (Cellular Reprogramming) for reprogramming of iPSC. NGS was performed at the Whitehead Genome Technology core (overseen by Sumeet Gupta). We thank Dr. Alexander Drew for helping with quality control of the PPMI and PDBP sub-cohorts of AMP-PD. E.H. was supported by the HSFP (LT000717/2015-L), NIH (R21NS112858), and Aligning Science Across Parkinson's disease(ASAP-000472). D.F. is supported by the Koerner New Scientist Program from the Koerner Family Foundation. We thank Dr. Leon French for assistance with computational code for enrichment term consolidation for the ROSMAP analysis. W.W. and C.L.M. are supported by the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer's Association as well as Alzheimer's Research UK (ARUK), the Michael J. Fox Foundation for Parkinson's Research (MJFF), and the Weston Brain Institute (Weston) (BAND-19-615151). S. Sunyaev is supported by NIH R01MH101244 and NIH R35GM127131. V.K. is a NYSCF Stem Cell Robertson Investigator (NYSCF-R-I49) and a George C. Cotzias Fellow of the American Parkinson's Disease Association; both awards supported this work. Additional grants to V.K. that supported this work include Aligning Science Across Parkinson's Inititiative ASAP-000472, Brigham Research Institute Director's Transformative Award, DOD W81XWH-19-1-0695, Michael J. Fox Foundation, Multiple System Atrophy Coalition, and NIH R21NS112858 and R01NS109209. The authors also thank the Accelerating Medicines Partnership Parkinson's disease (AMP PD), a public-private partnership, which is managed by the Foundation for the National Institutes of Health (FNIH) and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson's Research, the National Institute of Neurological Disorders and Stroke, Pfizer, and Verily. E.H. C.K. and V.K. conceived of and designed the project. E.H. and V.K. wrote the manuscript with input from co-authors. E.H. conducted and analyzed all biochemical and cell-based assays with help from Z.S. X.H.W. S. Sathyakumar, and A.V.; C.K. and E.H. conducted yeast assays. V.K. C.Y.C. and X.J. oversaw iPSC reprogramming and genetic corrections. J.S. constructed the Ngn2 piggyBac plasmid, and cell lines were generated by A.V.; X.D. analyzed sequencing data for the mRNA stability experiment. D.F. and P.L.D. conducted the ROSMAP analysis. W.W. and C.L.M. conducted the BridGE analysis. R.D.M. M.T.K. and J.T.G. contributed brain PLA. S.N. and S.R.S. designed and conducted RVTT analysis. S. Sarkar and M.B.F. conducted the Drosophila experiments. C.Y.C. designed and conducted the SILAC experiments, and N.D.U. D.R.M. and S.A.C. performed the mass spectrometry and downstream analysis. E.H. prepared all the figures and analyzed the data with input from V.K. (except as otherwise noted). V.K. is a co-founder of and senior advisor to DaCapo Brainscience and Yumanity Therapeutics, companies focused on CNS diseases. C.Y.C. and X.J. contributed to this work as employees of Yumanity Therapeutics. Funding Information: We thank all the members of ARCND community for their critical input on the paper, especially Drs. Dennis Selkoe, Greg Petsko, Ulf Dettmer, Charles Jennings, Vijay Kuchroo, Howard Weiner, and Tracy Young-Pearse. We thank Ulf Dettmer for the SNCA G51D construct, Lei Liu for PX459 plasmid, Lai Ding at BWH NeuroTechnology Studio for Fiji macros, Ping Xu at Yumanity Therapeutics for superb technical support, and Luigi Warren (Cellular Reprogramming) for reprogramming of iPSC. NGS was performed at the Whitehead Genome Technology core (overseen by Sumeet Gupta). We thank Dr. Alexander Drew for helping with quality control of the PPMI and PDBP sub-cohorts of AMP-PD. E.H. was supported by the HSFP ( LT000717/2015-L ), NIH ( R21NS112858 ), and Aligning Science Across Parkinson{\textquoteright}s disease ( ASAP-000472 ). D.F. is supported by the Koerner New Scientist Program from the Koerner Family Foundation . We thank Dr. Leon French for assistance with computational code for enrichment term consolidation for the ROSMAP analysis. W.W. and C.L.M. are supported by the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer{\textquoteright}s Association as well as Alzheimer{\textquoteright}s Research UK (ARUK), the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research (MJFF), and the Weston Brain Institute (Weston) ( BAND-19-615151 ). S. Sunyaev is supported by NIH R01MH101244 and NIH R35GM127131 . V.K. is a NYSCF Stem Cell Robertson Investigator ( NYSCF-R-I49 ) and a George C. Cotzias Fellow of the American Parkinson{\textquoteright}s Disease Association ; both awards supported this work. Additional grants to V.K. that supported this work include Aligning Science Across Parkinson{\textquoteright}s Inititiative ASAP-000472 , Brigham Research Institute Director's Transformative Award, DOD W81XWH-19-1-0695, Michael J. Fox Foundation , Multiple System Atrophy Coalition, and NIH R21NS112858 and R01NS109209 . The authors also thank the Accelerating Medicines Partnership Parkinson{\textquoteright}s disease (AMP PD), a public-private partnership, which is managed by the Foundation for the National Institutes of Health (FNIH) and funded by Celgene , GSK , the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research , the National Institute of Neurological Disorders and Stroke , Pfizer , and Verily . Funding Information: The authors thank the NIH-designated data repository (dbGaP: The database of Genotypes and Phenotypes), and the submitting investigators who submitted data from the original studies to the dbGap repository: phs000196.v3.p1 (Dr. Haydeh Payami), phs000089.v3.p2 (Dr. Robert Brown, Dr. David Simon, Dr. Dennis Dickson, Dr. Matthew Farrer, Dr. Emily Gorbold, Dr. Ira Shoulson, Dr. John A. Hardy, Dr. Laura Marsh, Dr. Michael Okun, Dr. Ted Roghstein, Dr. Zbigniew Wszolek), phs000048.v1.p1 (Dr. Demetrius M. Maraganore), phs000126.v2.p1(Dr. Tatiana Foroud, Dr. Richard H. Myers), phs000918.v1.p1 (Dr. Andrew B. Singleton, Dr. Mike A. Nalls), phs000394.v1.p1 (Dr. Jeffery Vance), phs000127.v2.p1 (Dr. Orla Hardiman, Dr. Brendan Loftus, Dr. Daniel G. Bradley, Dr. Alex Evans), phs000344.v1.p1 (Dr. Bryan J. Traynor, Dr. Pentti J. Tienari), phs000101.v3.p1 (Dr. Bryan J. Traynor), and their primary funding organizations including National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Institute on Aging, Michael J. Fox Foundation, International Parkinson Disease Genomics Consortium, USAMRAA, Muscular Dystrophy Association, Science Foundation Ireland, Microsoft Research, the ALS Association, The Helsinki University Central Hospital, the Finnish Academy, the Finnish Medical Society Duodecim, Kuopio University. The authors also thank the AMP PD, a public-private partnership, which is managed by the FNIH and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research, the National Institute of Neurological Disorders and Stroke, Pfizer, and Verily. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = jun,

day = "9",

doi = "10.1016/j.cell.2022.05.008",

language = "English (US)",

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pages = "2035--2056.e33",

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}

TY - JOUR

T1 - The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

AU - Hallacli, Erinc

AU - Kayatekin, Can

AU - Nazeen, Sumaiya

AU - Wang, Xiou H.

AU - Sheinkopf, Zoe

AU - Sathyakumar, Shubhangi

AU - Sarkar, Souvarish

AU - Jiang, Xin

AU - Dong, Xianjun

AU - Di Maio, Roberto

AU - Wang, Wen

AU - Keeney, Matthew T.

AU - Felsky, Daniel

AU - Sandoe, Jackson

AU - Vahdatshoar, Aazam

AU - Udeshi, Namrata D.

AU - Mani, D. R.

AU - Carr, Steven A.

AU - Lindquist, Susan

AU - De Jager, Philip L.

AU - Bartel, David P.

AU - Myers, Chad L.

AU - Greenamyre, J. Timothy

AU - Feany, Mel B.

AU - Sunyaev, Shamil R.

AU - Chung, Chee Yeun

AU - Khurana, Vikram

N1 - Funding Information: We thank all the members of ARCND community for their critical input on the paper, especially Drs. Dennis Selkoe, Greg Petsko, Ulf Dettmer, Charles Jennings, Vijay Kuchroo, Howard Weiner, and Tracy Young-Pearse. We thank Ulf Dettmer for the SNCA G51D construct, Lei Liu for PX459 plasmid, Lai Ding at BWH NeuroTechnology Studio for Fiji macros, Ping Xu at Yumanity Therapeutics for superb technical support, and Luigi Warren (Cellular Reprogramming) for reprogramming of iPSC. NGS was performed at the Whitehead Genome Technology core (overseen by Sumeet Gupta). We thank Dr. Alexander Drew for helping with quality control of the PPMI and PDBP sub-cohorts of AMP-PD. E.H. was supported by the HSFP (LT000717/2015-L), NIH (R21NS112858), and Aligning Science Across Parkinson's disease(ASAP-000472). D.F. is supported by the Koerner New Scientist Program from the Koerner Family Foundation. We thank Dr. Leon French for assistance with computational code for enrichment term consolidation for the ROSMAP analysis. W.W. and C.L.M. are supported by the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer's Association as well as Alzheimer's Research UK (ARUK), the Michael J. Fox Foundation for Parkinson's Research (MJFF), and the Weston Brain Institute (Weston) (BAND-19-615151). S. Sunyaev is supported by NIH R01MH101244 and NIH R35GM127131. V.K. is a NYSCF Stem Cell Robertson Investigator (NYSCF-R-I49) and a George C. Cotzias Fellow of the American Parkinson's Disease Association; both awards supported this work. Additional grants to V.K. that supported this work include Aligning Science Across Parkinson's Inititiative ASAP-000472, Brigham Research Institute Director's Transformative Award, DOD W81XWH-19-1-0695, Michael J. Fox Foundation, Multiple System Atrophy Coalition, and NIH R21NS112858 and R01NS109209. The authors also thank the Accelerating Medicines Partnership Parkinson's disease (AMP PD), a public-private partnership, which is managed by the Foundation for the National Institutes of Health (FNIH) and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson's Research, the National Institute of Neurological Disorders and Stroke, Pfizer, and Verily. E.H. C.K. and V.K. conceived of and designed the project. E.H. and V.K. wrote the manuscript with input from co-authors. E.H. conducted and analyzed all biochemical and cell-based assays with help from Z.S. X.H.W. S. Sathyakumar, and A.V.; C.K. and E.H. conducted yeast assays. V.K. C.Y.C. and X.J. oversaw iPSC reprogramming and genetic corrections. J.S. constructed the Ngn2 piggyBac plasmid, and cell lines were generated by A.V.; X.D. analyzed sequencing data for the mRNA stability experiment. D.F. and P.L.D. conducted the ROSMAP analysis. W.W. and C.L.M. conducted the BridGE analysis. R.D.M. M.T.K. and J.T.G. contributed brain PLA. S.N. and S.R.S. designed and conducted RVTT analysis. S. Sarkar and M.B.F. conducted the Drosophila experiments. C.Y.C. designed and conducted the SILAC experiments, and N.D.U. D.R.M. and S.A.C. performed the mass spectrometry and downstream analysis. E.H. prepared all the figures and analyzed the data with input from V.K. (except as otherwise noted). V.K. is a co-founder of and senior advisor to DaCapo Brainscience and Yumanity Therapeutics, companies focused on CNS diseases. C.Y.C. and X.J. contributed to this work as employees of Yumanity Therapeutics. Funding Information: We thank all the members of ARCND community for their critical input on the paper, especially Drs. Dennis Selkoe, Greg Petsko, Ulf Dettmer, Charles Jennings, Vijay Kuchroo, Howard Weiner, and Tracy Young-Pearse. We thank Ulf Dettmer for the SNCA G51D construct, Lei Liu for PX459 plasmid, Lai Ding at BWH NeuroTechnology Studio for Fiji macros, Ping Xu at Yumanity Therapeutics for superb technical support, and Luigi Warren (Cellular Reprogramming) for reprogramming of iPSC. NGS was performed at the Whitehead Genome Technology core (overseen by Sumeet Gupta). We thank Dr. Alexander Drew for helping with quality control of the PPMI and PDBP sub-cohorts of AMP-PD. E.H. was supported by the HSFP ( LT000717/2015-L ), NIH ( R21NS112858 ), and Aligning Science Across Parkinson’s disease ( ASAP-000472 ). D.F. is supported by the Koerner New Scientist Program from the Koerner Family Foundation . We thank Dr. Leon French for assistance with computational code for enrichment term consolidation for the ROSMAP analysis. W.W. and C.L.M. are supported by the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer’s Association as well as Alzheimer’s Research UK (ARUK), the Michael J. Fox Foundation for Parkinson’s Research (MJFF), and the Weston Brain Institute (Weston) ( BAND-19-615151 ). S. Sunyaev is supported by NIH R01MH101244 and NIH R35GM127131 . V.K. is a NYSCF Stem Cell Robertson Investigator ( NYSCF-R-I49 ) and a George C. Cotzias Fellow of the American Parkinson’s Disease Association ; both awards supported this work. Additional grants to V.K. that supported this work include Aligning Science Across Parkinson’s Inititiative ASAP-000472 , Brigham Research Institute Director's Transformative Award, DOD W81XWH-19-1-0695, Michael J. Fox Foundation , Multiple System Atrophy Coalition, and NIH R21NS112858 and R01NS109209 . The authors also thank the Accelerating Medicines Partnership Parkinson’s disease (AMP PD), a public-private partnership, which is managed by the Foundation for the National Institutes of Health (FNIH) and funded by Celgene , GSK , the Michael J. Fox Foundation for Parkinson’s Research , the National Institute of Neurological Disorders and Stroke , Pfizer , and Verily . Funding Information: The authors thank the NIH-designated data repository (dbGaP: The database of Genotypes and Phenotypes), and the submitting investigators who submitted data from the original studies to the dbGap repository: phs000196.v3.p1 (Dr. Haydeh Payami), phs000089.v3.p2 (Dr. Robert Brown, Dr. David Simon, Dr. Dennis Dickson, Dr. Matthew Farrer, Dr. Emily Gorbold, Dr. Ira Shoulson, Dr. John A. Hardy, Dr. Laura Marsh, Dr. Michael Okun, Dr. Ted Roghstein, Dr. Zbigniew Wszolek), phs000048.v1.p1 (Dr. Demetrius M. Maraganore), phs000126.v2.p1(Dr. Tatiana Foroud, Dr. Richard H. Myers), phs000918.v1.p1 (Dr. Andrew B. Singleton, Dr. Mike A. Nalls), phs000394.v1.p1 (Dr. Jeffery Vance), phs000127.v2.p1 (Dr. Orla Hardiman, Dr. Brendan Loftus, Dr. Daniel G. Bradley, Dr. Alex Evans), phs000344.v1.p1 (Dr. Bryan J. Traynor, Dr. Pentti J. Tienari), phs000101.v3.p1 (Dr. Bryan J. Traynor), and their primary funding organizations including National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Institute on Aging, Michael J. Fox Foundation, International Parkinson Disease Genomics Consortium, USAMRAA, Muscular Dystrophy Association, Science Foundation Ireland, Microsoft Research, the ALS Association, The Helsinki University Central Hospital, the Finnish Academy, the Finnish Medical Society Duodecim, Kuopio University. The authors also thank the AMP PD, a public-private partnership, which is managed by the FNIH and funded by Celgene, GSK, the Michael J. Fox Foundation for Parkinson’s Research, the National Institute of Neurological Disorders and Stroke, Pfizer, and Verily. Publisher Copyright: © 2022 The Authors

PY - 2022/6/9

Y1 - 2022/6/9

N2 - Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.

AB - Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.

KW - Lewy body disease

KW - Parkinson's disease

KW - Processing bodies

KW - RNA-binding proteins

KW - alpha-synuclein

KW - iPSC

KW - mRNA degradation

KW - mRNA stability

KW - rare variant

KW - synucleinopathy

UR - https://www.scopus.com/pages/publications/85131902675

UR - https://www.scopus.com/pages/publications/85131902675#tab=citedBy

U2 - 10.1016/j.cell.2022.05.008

DO - 10.1016/j.cell.2022.05.008

M3 - Article

C2 - 35688132

AN - SCOPUS:85131902675

SN - 0092-8674

VL - 185

SP - 2035-2056.e33

JO - Cell

JF - Cell

IS - 12

ER -

The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

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